Trial Outcomes & Findings for Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency (NCT NCT02004691)

NCT ID: NCT02004691

Last Updated: 2024-11-07

Results Overview

Percent predicted Hb and Altitude-adjusted DLco was calculated as: 100\*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) times Hemoglobin-adjusted factor times Altitude-adjustment factor.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

36 participants

Primary outcome timeframe

Baseline (Day 1)

Results posted on

2024-11-07

Participant Flow

The study was conducted at 23 active centers in 17 countries. A total of 62 participants were screened between 18 December 2015 and 22 October 2018, out of which 36 participants were randomized.

A total of 36 participants were randomized in a 1:1 ratio to receive either placebo or olipudase alfa in the primary analysis period (PAP) for 52 weeks. After completing PAP, participants entered an extension treatment period (ETP) where all participants received olipudase alfa up to Year 5.

Participant milestones

Participant milestones
Measure	Placebo Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
PAP: Up to 52 Weeks STARTED	18	18
PAP: Up to 52 Weeks COMPLETED	17	18
PAP: Up to 52 Weeks NOT COMPLETED	1	0
ETP: From Week 52 up to 5 Years STARTED	17	18
ETP: From Week 52 up to 5 Years COMPLETED	13	16
ETP: From Week 52 up to 5 Years NOT COMPLETED	4	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
PAP: Up to 52 Weeks Poor compliance	1	0
ETP: From Week 52 up to 5 Years Related to Coronavirus Disease (COVID-19)	1	0
ETP: From Week 52 up to 5 Years Withdrawal by Subject	1	1
ETP: From Week 52 up to 5 Years Pregnancy	1	0
ETP: From Week 52 up to 5 Years Adverse Event not Related to COVID-19	1	0
ETP: From Week 52 up to 5 Years Not Related to COVID-19	0	1

Baseline Characteristics

Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=18 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.	Total Title n=36 Participants
Age, Continuous	33.46 years STANDARD_DEVIATION 17.06 • n=5 Participants	36.17 years STANDARD_DEVIATION 12.72 • n=7 Participants	34.81 years STANDARD_DEVIATION 14.89 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	9 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	16 Participants n=5 Participants	16 Participants n=7 Participants	32 Participants n=5 Participants
Race/Ethnicity, Customized More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1)

Population: Analysis was performed on mITT population.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline	48.45 % Predicted DLco Standard Deviation 10.76	49.44 % Predicted DLco Standard Deviation 10.99

PRIMARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=17 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Percent Change From Baseline in Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Week 52	2.961 percent change Standard Error 3.3832	21.968 percent change Standard Error 3.3362

PRIMARY outcome

Timeframe: Baseline (Day 1)

Population: Analysis was performed on mITT population.

Spleen volume was assessed by abdominal magnetic resonance imaging (MRI) to quantitate the degree of splenomegaly in multiples of normal (MN).

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Combination Spleen Endpoint: Component 1: Spleen Volume (in MN) at Baseline	11.21 multiples of normal (MN) Standard Deviation 3.84	11.69 multiples of normal (MN) Standard Deviation 4.92

PRIMARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Spleen volume was assessed by abdominal MRI to quantitate the degree of splenomegaly in MN.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Combination Spleen Endpoint: Component 1: Percent Change From Baseline in Spleen Volume (in MN) at Week 52	0.481 percent change Standard Error 2.5002	-39.446 percent change Standard Error 2.4294

PRIMARY outcome

Timeframe: Baseline (Day 1)

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

The SRS rates 5 items: abdominal pain, abdominal discomfort, early satiety, dissatisfaction with abdominal body image, and difficulty to bend down using a numerical rating scale of 0 (absent) to 10 (worst imaginable). The total score of SRS ranges from 0 to 50, with higher scores (50) indicated worst imaginable rating. It was pre-specified as secondary endpoint for countries outside of US.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Combination Spleen Endpoint (Primary for US Only): Component 2: Splenomegaly-Related Score (SRS) at Baseline	28.05 score on a scale Standard Deviation 10.56	24.55 score on a scale Standard Deviation 11.13

PRIMARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=17 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Combination Spleen Endpoint (Primary for US Only): Component 2: Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52	-9.281 score on a scale Standard Error 2.4165	-7.664 score on a scale Standard Error 2.3481

SECONDARY outcome

Timeframe: From the first infusion of investigational medicinal product (IMP) up to 52 weeks

Population: The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).

An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Reported AEs are treatment-emergent AEs that developed, worsened or became serious during the treatment period.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52 TEAEs	18 Participants	18 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52 TESAEs	4 Participants	3 Participants

SECONDARY outcome

Timeframe: From the first infusion of IMP up to 52 weeks

Population: The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).

An AESI was defined as an AE (serious or nonserious) of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor was appropriate. AESIs included any pregnancy, symptomatic overdose, dose-limiting toxicities (DLTs) as defined in protocol and infusion associated reactions (IARs). Protocol-defined IARs were AEs that occurred during the infusion or within up to 24 hours after the start of infusion and were considered as related or possibly related to the study treatment by the investigator or the sponsor. Events occurring greater than or equal to (\>=) 24 hours after the start of an infusion might have been judged an IAR at the discretion of the investigator or sponsor. Algorithm-defined IARs were all AEs that started between the start of infusion and the end of infusion plus 24 hours, irrespective of the perceived relation with study treatment.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 Pregnancy	0 Participants	0 Participants
Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 Symptomatic Overdose	0 Participants	0 Participants
Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 DLTs	5 Participants	1 Participants
Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 Protocol-defined IARs	5 Participants	8 Participants
Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52 Algorithm-defined IARs	13 Participants	15 Participants

SECONDARY outcome

Timeframe: From Baseline (Day 1) up to 52 weeks

Population: The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).

PCSA criteria: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): \>3 x upper limit of normal (ULN), \>5 x ULN, \>10 x ULN and \>20 x ULN. Alkaline phosphatase (ALP) \> 1.5 x ULN. Total bilirubin \>1.5 x ULN and \>2 x ULN. ALT and total bilirubin: ALT \> 3 x ULN and total bilirubin \> 2 x ULN. Baseline was defined as the last non-missing value prior to the first infusion of study treatment.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 ALT: >3 x ULN	2 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 ALT: >5 x ULN	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 ALT: >10 x ULN	0 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 ALT: >20 x ULN	0 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 AST: >3 x ULN	2 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 AST: >5 x ULN	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 AST: >10 x ULN	0 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 AST: >20 x ULN	0 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 ALP: >1.5 x ULN	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 Total Bilirubin: >1.5 x ULN	4 Participants	4 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 Total Bilirubin: >2 x ULN	1 Participants	4 Participants
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52 ALT >3 x ULN and total bilirubin >2 x ULN	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 52

Population: The safety population was a subset of the randomized population and included randomized participants who received at least 1 infusion (partial or total).

Number of participants with treatment-emergent ADA are presented. Baseline was defined as the last non-missing value prior to the first infusion of study treatment.

Outcome measures

Outcome measures
Measure	Placebo n=18 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Number of Participants Who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52	1 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Liver volume was assessed by abdominal MRI in MN.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Percent Change From Baseline in Liver Volume (in MN) at Week 52	-1.468 percent change Standard Error 2.5409	-28.064 percent change Standard Error 2.4899

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=18 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Percent Change From Baseline in Platelet Counts at Week 52	2.490 percent change Standard Error 4.1923	16.822 percent change Standard Error 3.9596

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

The BFI is a 9-item, validated, self-administered questionnaire that was originally developed to assess fatigue severity. The 9-items were measured on a 0-10 scale, with 0 being 'does not interfere' and 10 being 'completely interferes.' BFI - Item 3 asks participants to "Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours. Numerical rating scale ranges from 0 (no fatigue) to 10 (worst imaginable fatigue). Higher global scores were associated with more severe fatigue.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=17 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Change From Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52	-1.806 score on a scale Standard Error 0.5272	-1.862 score on a scale Standard Error 0.5129

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF consisted of 15 items that use a numeric rating scale to assess pain severity and pain interference in the past 24 hours and the past week. For BPI-SF Item 3 asks participants to "Please rate your pain by marking the box beside the number that best describes your pain at its worst in the past 24 hours." The numeric rating scale ranged from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicate greater intensity of pain.

Outcome measures

Outcome measures
Measure	Placebo n=17 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=17 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Change From Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52	-2.293 score on a scale Standard Error 0.5899	-1.404 score on a scale Standard Error 0.5742

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

FACIT-Dyspnea is a 20 Item assessment that is split into two 10-item sections. The first 10-item section asks participants about the severity of their shortness of breath during various activities. The second 10-item section asks participants to rate the difficulty due to shortness of breath associated with the same activities that were referenced in the first section. For the dyspnea severity items, score range from 0=no shortness of breath; 1=mildly short of breath; 2=moderately short of breath; 3=severely short of breath. For the functional limitation items, score range from no difficult = 0, A little difficult = 1, some difficult = 2, and much difficulty =3. A raw score was calculated as: sum of individual item scores \* 10/number of items answered. Raw scores were then converted to scale scores using the table included in the FACIT Dyspnea Scale Short Form Scoring Guideline. FACIT dyspnea scale score ranged between 27.7 to 75.9. Higher score represented high levels of dyspnea.

Outcome measures

Outcome measures
Measure	Placebo n=11 Participants Participants received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Participants who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	Olipudase Alfa n=16 Participants Participants received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each participant underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Participants who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Change From Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52	-6.769 score on a scale Standard Error 1.9132	-5.862 score on a scale Standard Error 1.6918

Adverse Events

PAP: Placebo

Serious events: 4 serious events

Other events: 13 other events

Deaths: 0 deaths

PAP: Olipudase Alfa

Serious events: 3 serious events

Other events: 17 other events

Deaths: 0 deaths

ETP: Placebo/Olipudase Alfa

Serious events: 6 serious events

Other events: 9 other events

Deaths: 0 deaths

ETP: Olipudase Alfa/Olipudase Alfa

Serious events: 5 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	PAP: Placebo n=18 participants at risk Subjects received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52.	PAP: Olipudase Alfa n=18 participants at risk Subjects received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each subject underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0,3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP.	ETP: Placebo/Olipudase Alfa n=17 participants at risk Subjects who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.	ETP: Olipudase Alfa/Olipudase Alfa n=18 participants at risk Subjects who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
Infections and infestations Covid-19	0.00% 0/18 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	0.00% 0/18 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	41.2% 7/17 • Number of events 8 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	44.4% 8/18 • Number of events 9 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.
Infections and infestations Nasopharyngitis	33.3% 6/18 • Number of events 8 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	44.4% 8/18 • Number of events 18 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	29.4% 5/17 • Number of events 10 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	38.9% 7/18 • Number of events 22 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.
Infections and infestations Upper Respiratory Tract Infection	22.2% 4/18 • Number of events 6 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	33.3% 6/18 • Number of events 8 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	17.6% 3/17 • Number of events 7 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	16.7% 3/18 • Number of events 5 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.
Musculoskeletal and connective tissue disorders Arthralgia	16.7% 3/18 • Number of events 3 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	22.2% 4/18 • Number of events 10 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	17.6% 3/17 • Number of events 5 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	5.6% 1/18 • Number of events 2 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.
Nervous system disorders Headache	44.4% 8/18 • Number of events 32 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	66.7% 12/18 • Number of events 64 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	23.5% 4/17 • Number of events 48 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	27.8% 5/18 • Number of events 53 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.
Respiratory, thoracic and mediastinal disorders Cough	11.1% 2/18 • Number of events 3 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	27.8% 5/18 • Number of events 5 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	5.9% 1/17 • Number of events 2 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.	16.7% 3/18 • Number of events 3 • For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years Analysis was performed on safety population. MedDRA version 23.1 was used for PAP; whereas MedDRA version 26.0 was used for ETP data. Any non-serious AE with a preferred term in \>= 2 % participants and number of participants \>= 2 in the Olipudase Alfa group and the percentage of participants with the specific TEAE in the Olipudase Alfa group is greater than placebo group.

Additional Information

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